MicroRNAs as Oncogenes or Tumor Suppressors in Breast Cancer

Abdul Ahad Mehboob; Muqaddas; Muhammad Saqib; Aqsa Dastgir; Sabahat Mahnoor; Amna Noor; Ahmad Ashraf; Abdullah Habib; Alia

doi:10.70749/ijbr.v3i11.2608

Authors

Abdul Ahad Mehboob Pathology Department, The Christie NHS Foundation Trust, Manchester, United Kingdom
Muqaddas Department of Biochemistry, Abdul Wali Khan University Mardan, KP, Pakistan
Muhammad Saqib Institute of Microbiology, Government College University Faisalabad, Punjab, Pakistan
Aqsa Dastgir Center for Applied Molecular Biology and Forensics, Punjab University, Lahore, Punjab, Pakistan
Sabahat Mahnoor Pathology Department, Leeds Teaching Hospitals NHS Trust, United Kingdom
Amna Noor Department of Pathology, Rawalpindi Medical University, Rawalpindi, Punjab, Pakistan
Ahmad Ashraf Kausar Abdullah Malik School of Life Sciences, Forman Christian College University, Lahore, Pakistan
Abdullah Habib Department of Molecular Biology, University of Okara, Pakistan
Alia Department of Biochemistry, Abdul Wali Khan University Mardan, KP, Pakistan

DOI:

https://doi.org/10.70749/ijbr.v3i11.2608

Keywords:

Tumor, Oncogenic miRNAs, Exosomal miRNA, CRISPR, Breast Cancer.

Abstract

MicroRNAs (miRNAs) are increasingly recognized as key regulators of gene expression in breast cancer as either an oncomir (oncogene) or a tumor suppressor. This article aims to provide an overview of the conflicting roles of miRNAs in breast cancer initiation and progression and response to treatment. Oncogenic miRNAs, such as miR-21, miR-155, and miR-221/222, promote tumorigenesis by targeting primary tumor suppressor pathways, while antitumor miRNAs (tumor suppressors),, including the miR-34 family, miR-200 family and miR-145, inhibit cancer progression by modulating oncogenic signaling networks. We will examine miRNA biogenesis pathways and miRNAs' context-dependent roles, including diagnostic biomarkers and therapeutic targets. We conclude with a discussion on subtype-specific signatures of miRNAs, exosomal miRNA content and emerging technologies, such as single-cell miRNA sequencing and CRISPR-based editing that will enhance understanding of the biology of miRNAs in breast cancer.

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References

1. Sung, H., Ferlay, J., Siegel, R. L., Laversanne, M., Soerjomataram, I., Jemal, A., & Bray, F. (2021). Global cancer statistics 2020: Globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians, 71(3), 209-249.

https://doi.org/10.3322/caac.21660

2. Bartel, D. P. (2018). Metazoan MicroRNAs. Cell, 173(1), 20-51.

https://doi.org/10.1016/j.cell.2018.03.006

3. Khalid, A. K., Hafeez, F., Qalandar, S., Fatima, H., Saqib, M., Ali, U., Imran, F., Awais, H. M., Faizan, M., & Hussain, A. (2024). Microbial biomarkers helpful in early detection of cancer: Prognosis and suitable treatment. Indus Journal of Bioscience Research, 2(2), 903-917.

https://doi.org/10.70749/ijbr.v2i02.296

4. Hayes, J., Peruzzi, P. P., & Lawler, S. (2014). MicroRNAs in cancer: Biomarkers, functions and therapy. Trends in Molecular Medicine, 20(8), 460-469.

https://doi.org/10.1016/j.molmed.2014.06.005

5. Lu, J., Getz, G., Miska, E. A., Alvarez-Saavedra, E., Lamb, J., Peck, D., Sweet-Cordero, A., Ebert, B. L., Mak, R. H., Ferrando, A. A., Downing, J. R., Jacks, T., Horvitz, H. R., & Golub, T. R. (2005). MicroRNA expression profiles classify human cancers. Nature, 435(7043), 834-838.

https://doi.org/10.1038/nature03702

6. Ha, M., & Kim, V. N. (2014). Regulation of microRNA biogenesis. Nature Reviews Molecular Cell Biology, 15(8), 509-524.

https://doi.org/10.1038/nrm3838

7. Hammond, S. M. (2015). An overview of microRNAs. Advanced Drug Delivery Reviews, 87, 3-14.

https://doi.org/10.1016/j.addr.2015.05.001

8. Stavast, C., & Erkeland, S. (2019). The non-canonical aspects of MicroRNAs: Many roads to gene regulation. Cells, 8(11), 1465.

https://doi.org/10.3390/cells8111465

9. Abdelfattah, A. M., Park, C., & Choi, M. Y. (2014). Update on non-canonical microRNAs. Biomolecular Concepts, 5(4), 275-287.

https://doi.org/10.1515/bmc-2014-0012

10. Lujambio, A., Calin, G. A., Villanueva, A., Ropero, S., Sánchez-Céspedes, M., Blanco, D., Montuenga, L. M., Rossi, S., Nicoloso, M. S., Faller, W. J., Gallagher, W. M., Eccles, S. A., Croce, C. M., & Esteller, M. (2008). A microRNA DNA methylation signature for human cancer metastasis. Proceedings of the National Academy of Sciences, 105(36), 13556-13561.

https://doi.org/10.1073/pnas.0803055105

11. Kumar, M. S., Pester, R. E., Chen, C. Y., Lane, K., Chin, C., Lu, J., Kirsch, D. G., Golub, T. R., & Jacks, T. (2009). Dicer1 functions as a haploinsufficient tumor suppressor. Genes & Development, 23(23), 2700-2704.

https://doi.org/10.1101/gad.1848209

12. Jonas, S., & Izaurralde, E. (2015). Towards a molecular understanding of microrna-mediated gene silencing. Nature Reviews Genetics, 16(7), 421-433.

https://doi.org/10.1038/nrg3965

13. Gebert, L. F., & MacRae, I. J. (2018). Regulation of microRNA function in animals. Nature Reviews Molecular Cell Biology, 20(1), 21-37.

https://doi.org/10.1038/s41580-018-0045-7

14. Saito, Y., & Jones, P. M. (2006). Epigenetic activation of tumor suppressor MicroRNAs in human cancer cells. Cell Cycle, 5(19), 2220-2222.

https://doi.org/10.4161/cc.5.19.3340

15. Van Niel, G., D'Angelo, G., & Raposo, G. (2018). Shedding light on the cell biology of extracellular vesicles. Nature Reviews Molecular Cell Biology, 19(4), 213-228.

https://doi.org/10.1038/nrm.2017.125

16. Tay, Y., Rinn, J., & Pandolfi, P. P. (2014). The multilayered complexity of Cerna crosstalk and competition. Nature, 505(7483), 344-352.

https://doi.org/10.1038/nature12986

17. Agarwal, V., Bell, G. W., Nam, J., & Bartel, D. P. (2015). Predicting effective microRNA target sites in mammalian mRNAs.

https://doi.org/10.7554/elife.05005.028

18. Faizan, M., Hussain, A., Nadeem, Z., Tariq, A., Arif, M. I., Chorahi, M. U., Shabbir, L., Mustafa, S., & Ghaffar, M. (2025). Revolutionizing oncology: Harnessing artificial intelligence for precision tumor detection and personalized treatment with Microbiological insight. Indus Journal of Bioscience Research, 3(6), 592-597.

https://doi.org/10.70749/ijbr.v3i6.1710

19. Chi, S. W., Zang, J. B., Mele, A., & Darnell, R. B. (2009). Argonaute HITS-CLIP decodes microrna–mrna interaction maps. Nature, 460(7254), 479-486.

https://doi.org/10.1038/nature08170

20. Esquela-Kerscher, A., & Slack, F. J. (2006). Oncomirs — microRNAs with a role in cancer. Nature Reviews Cancer, 6(4), 259-269.

https://doi.org/10.1038/nrc1840

21. Chi, S. W., Zang, J. B., Mele, A., & Darnell, R. B. (2009). Argonaute HITS-CLIP decodes microrna–mrna interaction maps. Nature, 460(7254), 479-486.

https://doi.org/10.1038/nature08170

22. Bhome, R., Del Vecchio, F., Lee, G., Bullock, M. D., Primrose, J. N., Sayan, A. E., & Mirnezami, A. H. (2018). Exosomal microRNAs (exomiRs): Small molecules with a big role in cancer. Cancer Letters, 420, 228-235.

https://doi.org/10.1016/j.canlet.2018.02.002

23. Lowery, A. J., Miller, N., Devaney, A., McNeill, R. E., Davoren, P. A., Lemetre, C., Benes, V., Schmidt, S., Blake, J., Ball, G., & Kerin, M. J. (2009). MicroRNA signatures predict oestrogen receptor, progesterone receptor and HER2/neureceptor status in breast cancer. Breast Cancer Research, 11(3).

https://doi.org/10.1186/bcr2257

24. Adams, B., Kasinski, A., & Slack, F. (2014). Aberrant regulation and function of MicroRNAs in cancer. Current Biology, 24(16), R762-R776.

https://doi.org/10.1016/j.cub.2014.06.043

25. Kent, O. A., & Mendell, J. T. (2006). A small piece in the cancer puzzle: MicroRNAs as tumor suppressors and oncogenes. Oncogene, 25(46), 6188-6196.

https://doi.org/10.1038/sj.onc.1209913

26. Iorio, M. V., Ferracin, M., Liu, C., Veronese, A., Spizzo, R., Sabbioni, S., Magri, E., Pedriali, M., Fabbri, M., Campiglio, M., Ménard, S., Palazzo, J. P., Rosenberg, A., Musiani, P., Volinia, S., Nenci, I., Calin, G. A., Querzoli, P., Negrini, M., … Croce, C. M. (2005). MicroRNA gene expression deregulation in human breast cancer. Cancer Research, 65(16), 7065-7070.

https://doi.org/10.1158/0008-5472.can-05-1783

27. Hermeking, H. (2009). The Mir-34 family in cancer and apoptosis. Cell Death & Differentiation, 17(2), 193-199.

https://doi.org/10.1038/cdd.2009.56

28. Gregory, P. A., Bracken, C. P., Bert, A. G., & Goodall, G. J. (2008). MicroRNAs as regulators of epithelial-mesenchymal transition. Cell Cycle, 7(20), 3112-3117.

https://doi.org/10.4161/cc.7.20.6851

29. Boyerinas, B., Park, S., Hau, A., Murmann, A. E., & Peter, M. E. (2010). The role of let-7 in cell differentiation and cancer. Endocrine-Related Cancer, 17(1), F19-F36.

https://doi.org/10.1677/erc-09-0184

30. Scott, G. K., Goga, A., Bhaumik, D., Berger, C. E., Sullivan, C. S., & Benz, C. C. (2007). Coordinate suppression of ERBB2 and ERBB3 by enforced expression of Micro-RNA Mir-125a or Mir-125b. Journal of Biological Chemistry, 282(2), 1479-1486.

https://doi.org/10.1074/jbc.m609383200

31. Zhang, B., Pan, X., Cobb, G. P., & Anderson, T. A. (2007). MicroRNAs as oncogenes and tumor suppressors. Developmental Biology, 302(1), 1-12.

https://doi.org/10.1016/j.ydbio.2006.08.028

32. Aqeilan, R. I., Calin, G. A., & Croce, C. M. (2009). Mir-15a and Mir-16-1 in cancer: Discovery, function and future perspectives. Cell Death & Differentiation, 17(2), 215-220.

https://doi.org/10.1038/cdd.2009.69

33. Tavazoie, S. F., Alarcón, C., Oskarsson, T., Padua, D., Wang, Q., Bos, P. D., Gerald, W. L., & Massagué, J. (2008). Endogenous human microRNAs that suppress breast cancer metastasis. Nature, 451(7175), 147-152.

https://doi.org/10.1038/nature06487

34. Wang, Y., Huang, J., Li, M., Cavenee, W. K., Mitchell, P. S., Zhou, X., Tewari, M., Furnari, F. B., & Taniguchi, T. (2011). Microrna-138 modulates DNA damage response by repressing histone H2AX expression. Molecular Cancer Research, 9(8), 1100-1111.

https://doi.org/10.1158/1541-7786.mcr-11-0007

35. Bhat-Nakshatri, P., Wang, G., Collins, N. R., Thomson, M. J., Geistlinger, T. R., Carroll, J. S., Brown, M., Hammond, S., Srour, E. F., Liu, Y., & Nakshatri, H. (2009). Estradiol-regulated microRNAs control estradiol response in breast cancer cells. Nucleic Acids Research, 37(14), 4850-4861.

https://doi.org/10.1093/nar/gkp500

36. Riaz, M., Van Jaarsveld, M. T., Hollestelle, A., Prager-van der Smissen, W. J., Heine, A. A., Boersma, A. W., Liu, J., Helmijr, J., Ozturk, B., Smid, M., Wiemer, E. A., Foekens, J. A., & Martens, J. W. (2013). MiRNA expression profiling of 51 human breast cancer cell lines reveals subtype and driver mutation-specific miRNAs. Breast Cancer Research, 15(2).

https://doi.org/10.1186/bcr3415

37. Bader, A. G. (2012). Mir-34 – a microRNA replacement therapy is headed to the clinic. Frontiers in Genetics, 3.

https://doi.org/10.3389/fgene.2012.00120

38. Cortez, M. A., Valdecanas, D., Zhang, X., Zhan, Y., Bhardwaj, V., Calin, G. A., Komaki, R., Giri, D. K., Quini, C. C., Wolfe, T., Peltier, H. J., Bader, A. G., Heymach, J. V., Meyn, R. E., & Welsh, J. W. (2014). Therapeutic delivery of Mir-200c enhances Radiosensitivity in lung cancer. Molecular Therapy, 22(8), 1494-1503.

https://doi.org/10.1038/mt.2014.79

39. Greene, S. B., Gunaratne, P. H., Hammond, S. M., & Rosen, J. M. (2010). A putative role for microrna-205 in mammary epithelial cell progenitors. Journal of Cell Science, 123(4), 606-618.

https://doi.org/10.1242/jcs.056812

40. Hwang, H., Wentzel, E. A., & Mendell, J. T. (2007). A Hexanucleotide element directs MicroRNA nuclear import. Science, 315(5808), 97-100.

https://doi.org/10.1126/science.1136235

41. Chivukula, R. R., & Mendell, J. T. (2008). Circular reasoning: MicroRNAs and cell-cycle control. Trends in Biochemical Sciences, 33(10), 474-481.

https://doi.org/10.1016/j.tibs.2008.06.008

42. Huang, X., Le, Q., & Giaccia, A. J. (2010). Mir-210 – micromanager of the hypoxia pathway. Trends in Molecular Medicine, 16(5), 230-237.

https://doi.org/10.1016/j.molmed.2010.03.004

43. O'Connell, R. M., Rao, D. S., Chaudhuri, A. A., & Baltimore, D. (2010). Physiological and pathological roles for microRNAs in the immune system. Nature Reviews Immunology, 10(2), 111-122.

https://doi.org/10.1038/nri2708

44. Tsang, J., Zhu, J., & Van Oudenaarden, A. (2007). Microrna-mediated feedback and Feedforward loops are recurrent network motifs in mammals. Molecular Cell, 26(5), 753-767.

https://doi.org/10.1016/j.molcel.2007.05.018

45. Le, T. D., Zhang, J., Liu, L., & Li, J. (2015). Ensemble methods for MiRNA target prediction from expression data. PLOS ONE, 10(6), e0131627.

https://doi.org/10.1371/journal.pone.0131627

46. Valadi, H., Ekström, K., Bossios, A., Sjöstrand, M., Lee, J. J., & Lötvall, J. O. (2007). Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nature Cell Biology, 9(6), 654-659.

https://doi.org/10.1038/ncb1596

47. Zhang, L., Zhang, S., Yao, J., Lowery, F. J., Zhang, Q., Huang, W., Li, P., Li, M., Wang, X., Zhang, C., Wang, H., Ellis, K., Cheerathodi, M., McCarty, J. H., Palmieri, D., Saunus, J., Lakhani, S., Huang, S., Sahin, A. A., … Yu, D. (2015). Microenvironment-induced PTEN loss by exosomal microRNA primes brain metastasis outgrowth. Nature, 527(7576), 100-104.

https://doi.org/10.1038/nature15376

48. Hannafon, B., & Ding, W. (2013). Intercellular communication by exosome-derived microRNAs in cancer. International Journal of Molecular Sciences, 14(7), 14240-14269.

https://doi.org/10.3390/ijms140714240

49. Kamerkar, S., LeBleu, V. S., Sugimoto, H., Yang, S., Ruivo, C. F., Melo, S. A., Lee, J. J., & Kalluri, R. (2017). Exosomes facilitate therapeutic targeting of oncogenic KRAS in pancreatic cancer. Nature, 546(7659), 498-503.

https://doi.org/10.1038/nature22341

50. Zhao, H., Shen, J., Medico, L., Wang, D., Ambrosone, C. B., & Liu, S. (2010). A pilot study of circulating miRNAs as potential biomarkers of early stage breast cancer. PLoS ONE, 5(10), e13735.

https://doi.org/10.1371/journal.pone.0013735

51. Wu, X., Somlo, G., Palomares, M., Yen, Y., Rossi, J., Gao, H., & Wang, S. E. (2012). De Novo sequencing of circulating microRNAs identifies novel markers predicting clinical outcome of locally advanced breast cancer. Cancer Research, 72(2_Supplement), A9-A9.

https://doi.org/10.1158/1538-7445.nonrna12-a9

52. Ibrahim, A. F., Weirauch, U., Thomas, M., Grünweller, A., Hartmann, R. K., & Aigner, A. (2011). MicroRNA replacement therapy for Mir-145 and Mir-33a is efficacious in a model of colon carcinoma. Cancer Research, 71(15), 5214-5224.

https://doi.org/10.1158/0008-5472.can-10-4645

53. Van Rooij, E., & Kauppinen, S. (2014). Development of micro RNA therapeutics is coming of age. EMBO Molecular Medicine, 6(7), 851-864.

https://doi.org/10.15252/emmm.201100899

54. Chen, Y., & Wang, X. (2019). MiRDB: An online database for prediction of functional microRNA targets. Nucleic Acids Research, 48(D1), D127-D131.

https://doi.org/10.1093/nar/gkz757

55. Ståhl, P. L., Salmén, F., Vickovic, S., Lundmark, A., Navarro, J. F., Magnusson, J., Giacomello, S., Asp, M., Westholm, J. O., Huss, M., Mollbrink, A., Linnarsson, S., Codeluppi, S., Borg, Å., Pontén, F., Costea, P. I., Sahlén, P., Mulder, J., Bergmann, O., … Frisén, J. (2016). Visualization and analysis of gene expression in tissue sections by spatial transcriptomics. Science, 353(6294), 78-82.

https://doi.org/10.1126/science.aaf2403

56. Joung, J., Konermann, S., Gootenberg, J. S., Abudayyeh, O. O., Platt, R. J., Brigham, M. D., Sanjana, N. E., & Zhang, F. (2017). Genome-scale CRISPR-cas9 knockout and transcriptional activation screening. Nature Protocols, 12(4), 828-863.

https://doi.org/10.1038/nprot.2017.016

57. Thakore, P. I., D'Ippolito, A. M., Song, L., Safi, A., Shivakumar, N. K., Kabadi, A. M., Reddy, T. E., Crawford, G. E., & Gersbach, C. A. (2015). Highly specific epigenome editing by CRISPR-cas9 repressors for silencing of distal regulatory elements. Nature Methods, 12(12), 1143-1149.

https://doi.org/10.1038/nmeth.3630

58. Wang, F., Flanagan, J., Su, N., Wang, L., Bui, S., Nielson, A., Wu, X., Vo, H., Ma, X., & Luo, Y. (2012). RNAscope. The Journal of Molecular Diagnostics, 14(1), 22-29.

https://doi.org/10.1016/j.jmoldx.2011.08.002

59. Ching, T., Himmelstein, D. S., Beaulieu-Jones, B. K., Kalinin, A. A., Do, B. T., Way, G. P., Ferrero, E., Agapow, P., Zietz, M., Hoffman, M. M., Xie, W., Rosen, G. L., Lengerich, B. J., Israeli, J., Lanchantin, J., Woloszynek, S., Carpenter, A. E., Shrikumar, A., Xu, J., … Greene, C. S. (2017). Opportunities and obstacles for deep learning in biology and medicine.

https://doi.org/10.1101/142760

60. Agarwal, V., Bell, G. W., Nam, J., & Bartel, D. P. (2015). Author response: Predicting effective microRNA target sites in mammalian mRNAs.

https://doi.org/10.7554/elife.05005.028

61. Popova, M., Isayev, O., & Tropsha, A. (2018). Deep reinforcement learning for de Novo drug design. Science Advances, 4(7).

https://doi.org/10.1126/sciadv.aap7885

62. Hasin, Y., Seldin, M., & Lusis, A. (2017). Multi-omics approaches to disease. Genome Biology, 18(1).

https://doi.org/10.1186/s13059-017-1215-1

63. PIVA, R., SPANDIDOS, D. A., & GAMBARI, R. (2013). From microRNA functions to microRNA therapeutics: Novel targets and novel drugs in breast cancer research and treatment. International Journal of Oncology, 43(4), 985-994.

https://doi.org/10.3892/ijo.2013.2059

64. Garofalo, M., & Croce, C. M. (2013). MicroRNAs as therapeutic targets in chemoresistance. Drug Resistance Updates, 16(3-5), 47-59.

https://doi.org/10.1016/j.drup.2013.05.001

65. Paul, B., Barnes, S., Demark-Wahnefried, W., Morrow, C., Salvador, C., Skibola, C., & Tollefsbol, T. O. (2015). Influences of diet and the gut microbiome on epigenetic modulation in cancer and other diseases. Clinical Epigenetics, 7(1).

https://doi.org/10.1186/s13148-015-0144-7

66. Wang, H., Tan, G., Dong, L., Cheng, L., Li, K., Wang, Z., & Luo, H. (2012). Circulating Mir-125b as a marker predicting Chemoresistance in breast cancer. PLoS ONE, 7(4), e34210.

https://doi.org/10.1371/journal.pone.0034210